Understand the key values that underpin research ethics
Understand the structure and process for ethical review of human research in Australia
Appreciate some of the challenging ethical issues that arise from human research
Much of the regulation surrounding clinical research is a response to bad things done in the name of research
Clinical research needs to be good science, respect participants, and fair.
Human Research Ethics Committees, a committee of researchers, health professionals and community representatives, review and approve clinical research against the National Statement
Clinical research poses interesting and often difficult ethical questions.
| 1932 | Tuskegee starts |
| 1941–5 | Nazi medical trials |
| 1947 | Nuremberg Code |
| 1964 | Declaration of Helsinki |
| 1972 | Tuskegee is terminated |
| 1999 | Alder Hey organ retention scandal |
A forty-year study on the natural history of syphilis conducted by the US Public Health Service from 1932–1972.
In 1932 the therapies used for syphilis were ineffective and toxic.
By 1947 penicillin was available and being used effectively across the US, but study researchers prevented subjects from receiving treatment.
In 1966 the study was still being supported by the Center for Disease Control and local chapters of the American Medical Association.
The study is terminated following media reports and a public outcry in 1972.
Respect for Autonomy: respect the rights and dignity of individuals
Beneficence: help people
Non-maleficence: do no harm
Justice: treat people fairly
Merit and integrity of the research: conduct good studies well
Respect for Autonomy: respect the rights and dignity of individuals
Beneficence: help people
Non-maleficence: do no harm
Justice: treat people fairly
The Declaration of Helsinki has been incorporated into local law and practice in most countries
Central to the system is a committee composed of experts and community representatives, these are called Institutional Review Boards (IRBs) in the US and Human Research Ethics Committees (HRECs) here
All human research needs ethical review. All human research that has the potential to cause anything more than minor discomfort needs to be reviewed by a HREC
Minimum of 8 people, ideally equal men and women with a third of the committee external to the institution
At least:
(National Statement, 81–1)
Research has to be good science to be ethical. Research with merit
aims to fill gaps in our knowledge
is well designed to answer its aims
Integrity refers to the way that the research is conducted. There is a genuine search for knowledge and understanding, the research is conducted honestly, and the results are distributed regardless of outcome
The potential benefits of research need to outweigh the risks
The benefits of the research may accrue to people other than those involved in the study
The risks involved in some studies is great, what is important is that the risks are considered, minimised and clearly explained
Respect people involved in research, including: their welfare, beliefs, cultural heritage, perceptions and customs
Respect the capacity people have to make their own decisions about participation
Respect people unable to make their own decisions, empower them to be as involved as possible and protect them by involving people who can advocate on their behalf
Participation in research is voluntary. Due respect for participants requires informed consent.
People need to be given enough information about the study to be able to decide whether to participate.
The effect of unequal power in relationships should be considered.
The need for informed consent may be waived in specific circumstances
‘Specific’ to a particular project
‘Extended’ to future projects that are an extension of the present project or very similar
‘Unspecified’ data and/or tissue (usually de-identified) may be used in any future research
Are the inclusion and exclusion criteria for the study fair given the objectives of the research? (Unfair exclusion is more common than unfair inclusion)
Are the burdens on participation on particular groups reasonable?
Is there fair access to the benefits of research?
Bartlett et al. (1985) was designed to prove ECMO was effective in these patients.
The study enrolled infants judged to have \(\ge\) 80% mortality rate. Only infants receiving ECMO provided informed consent.
Randomised-play-the-winner design; more infants were to be recruited to whichever treatment arm was the more successful. Planned to stop after 10 survivors or 10 deaths.
Overall 1 control patient (who died) and 11 ECMO patients (who survived). A further 8 patients were given ECMO and survived.
The importance of research on vulnerable populations
The importance of informed consent. Do you think it was appropriate that only parents of infants that received ECMO gave informed consent to participate?
What standard should be used by clinicians to decide whether or not they should enrol their patient in research?
randomization is acceptable when the clinician-investigator is indifferent between the randomized treatments for the patient (Royall, 2008)
randomization is acceptable when there is no consensus within the clinical community as to which of the randomized treatments is best for the patient (or group of patients) (Freedman, 1987)
Depression in children and adolescents is common
Treatment with SSRIs and other antidepressants has been relatively common
But only very limited research has been conducted on the use of antidepressants in children and adolescents. There is considerable controversy about both efficacy and safety.
Which principle of research ethics does this situation violate?
Developing new oncology treatments
First use in humans is typically on cancer patients with poor prognosis, e.g. expected survival without treatment may be 3 months and best-case survival on treatment up to 5 months
The new treatments carry significant risks, not all of them known and the studies may include a range of additional invasive procedures
In a randomized study treatment or control is decided by chance.
Dose escalation trial in chronic phase CML patients in whom interferon-\(\alpha\) treatment had failed. Prognosis is poor, life expectancy measured in months.
83 patients successively assigned to 1 of 14 dose cohorts, ranging from 25mg–1000mg per day
53 of the 54 patients on \(\ge\) 300mg/day had a complete haematological response (reduced WBC and platelet count maintained for four weeks). 51 of these patients maintained this response up to 265 days.
The standard view has been that trial data is owned by whomever conducted the study. That view is changing.
More publishers are stipulating that data is made available following clinical trials of medicines and devices, see for example Godlee & Groves (2012).
Oseltamivir is approved for use in influenza and is recommended by the World Health Organisation, the US Centers for Disease Control and Prevention, and many more
It is recommended (and stockpiled) in many countries based on the belief that oseltamivir reduces complication associated with influenza
Despite this many of the Phase III trials conducted with oseltamivir remain unpublished
The BMJ held a public campaign to improve access to data on oseltamivir: http://www.bmj.com/tamiflu
Oseltamivir data and published reports
Jefferson et al. (2014) provides a rigourous meta-analysis of oseltamivir data (full clinical trial reports, case reports, etc)
Benefits of oseltamivir on influenza are modest: shorter time to first alleviation of symptoms (16.8 hours, 95% confidence interval 8.4–25.1)
Limited compelling data on complications (e.g. pneumonia, hospitalisation and death)
Bartlett, R. H., Andrews, A. F., Toomasian, J. M., Haiduc, N. J., & Gazzaniga, A. B. (1982). Extracorporeal membrane oxygenation for newborn respiratory failure: forty-five cases. Surgery, 92(2), 425–433.
Bartlett, R. H., Roloff, D. W., Cornell, R. G., Andrews, A. F., Dillon, P. W., Zwischenberger, J. B., Ware, J. H., & Epstein, M. F. (1985). Extracorporeal circulation in neonatal respiratory failure: a prospective randomized study. Pediatrics, 76(4), 479–487.
Druker, B. J., Talpaz, M., Resta, D. J., & Al, E. (2001). Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. The New England Journal of Medicine, 344(14), 1031–1037.
Freedman, B. (1987). Equipoise and the ethics of clinical research. The New England Journal of Medicine, 317(3), 141–145.
Godlee, F., & Groves, T. (2012). The new BMJ policy on sharing data from drug and device trials. BMJ (Clinical Research Ed), 345(nov20 3), e7888–e7888. https://doi.org/10.1136/bmj.e7888
Jefferson, T., Jones, M., Doshi, P., Spencer, E. A., Onakpoya, I., & Heneghan, C. J. (2014). Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ (Clinical Research Ed), 348(apr09 2), g2545–g2545. https://doi.org/10.1136/bmj.g2545
Peto, R., & Biagent, C. (1998). Trials: The next 50 years. Large scale randomised evidence of moderate benefits. British Medical Journal, 317(7167), 1170–1171.
Pocock, S. J. (1993). Statistical and ethical issues in monitoring clinical trials. Statistics in Medicine, 12(15-16), 1455–1459. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Retrieve&list_uids=8248657&dopt=abstractplus
Royall, R. M. (2008). Ethics and statistics in randomized clinical trials. Statistical Science, 6(1), 52–62.